The overarching goal of the Fox lab is the study of metabolic risk factors and cardiovascular disease. As such, Dr. Fox works in three major content areas: obesity, diabetes, and chronic kidney disease (CKD). Her work spans traditional population science and genetic epidemiology. Obesity, Ectopic Fat, and Vascular Disease In terms of obesity, Dr. Fox has created a computed-tomography body composition database by using standard imaging techniques to assess abdominal visceral fat, pericardial fat, mediastinal fat, perivascular fat, fatty liver, and renal sinus fat. Her work focuses on both the systemic and local manifestations of body fat distribution, working with the concept that fat can have locally toxic effects on the vasculature and nearby anatomic structures. A cornerstone of Dr. Foxs work in this area has revolved around the mentoring of students, pre-doctoral fellows, post-doctoral fellows, and junior faculty members. These datasets have resulted in 9 publications in the past year. Dr. Fox is also involved in the genetics and genomics of obesity and body composition. She leads the CHARGE adiposity group, and is an active participant in the GIANT consortium, a genome-wide association consortium dedicated to uncovering genomic loci for anthropometric traits. The GIANT consortium has recently uncovered 14 new loci for body fat distribution and 18 new loci for body mass index. Dr. Fox has also conducted GWAS of visceral and pericardial fat, which have also revealed unique loci for ectopic fat distribution. As part of the CHARGE-S consortium, sequencing is ongoing for generalized obesity and body composition. A major new publication this year in the area of ectopic fat was examining the association between renal sinus fat and hypertension and CKD. Ectopic fat depots may mediate local and systemic disease. Animal models of diet-induced obesity demonstrate increased fat accumulation in the renal sinus. The association of renal sinus fat with hypertension, CKD, and other metabolic disorders has not been studied in a large, community-based sample. Participants from the Framingham Heart Study underwent quantification of renal sinus fat area using computed tomography. Multivariable linear and logistic regression was used to model metabolic risk factors as a function of fatty kidney and log-transformed renal sinus fat. We observed no association between fatty kidney and diabetes after adjusting for VAT. In conclusion, fatty kidney is a common condition that is associated with an increased risk of hypertension and chronic kidney disease. Renal sinus fat may play a role in blood pressure regulation and CKD. Chronic Kidney Disease Dr. Fox also works to understand the role of chronic kidney disease. Dr. Fox is interested in traditional and novel risk factors for chronic kidney disease. Chronic kidney disease is an important risk factor for heart disease, and often is undetected. Thus, improving our ability to detect and predict chronic kidney disease is an important scientific goal. The Fox lab has recently developed a renal risk score, and showed that standard clinical risk factors including age, hypertension, diabetes, and proteinuria can improve our ability to predict who will develop kidney disease within a 10-year interval. An important publication this year examined a multi-marker biomarker panel and its ability to predict incident CKD and microalbuminuria. Traditional risk factors do not adequately identify individuals at risk CKD. Newer biomarkers may improve prediction of CKD risk. We related a multi-marker panel consisting of the following 7 circulating biomarkers to the incidence of CKD and microalbuminuria (MA): C-reactive protein, aldosterone, renin, B-type natriuretic peptide (BNP), plasminogen-activator inhibitor type 1, fibrinogen, and homocysteine. We identified a parsimonious set of markers related to the outcomes adjusting for standard risk factors and baseline renal function and assessed their incremental predictive utility. On follow-up, 213 participants developed CKD, and 186 developed microalbuminuria (MA). Additional work was done using multivariable and reclassification models. Urinary biomarkers can provide insight into risk prediction, but also provide information regarding the location of renal injury, which may have prognostic significance. The Fox lab is now examining a panel of 14 urinary biomarkers. Parallel to epidemiologic and biomarker work, Dr. Fox leads the CHARGE and CARe renal working groups, two consortia which focus on the genetics of renal function. Dr. Fox is also the founder and convener of CKDGen, an international consortium dedicated to uncovering genes for renal disease. CKDGen includes more than 35 participating studies with over 100,000 individual participants and 150 investigators. This group is rapidly working to uncover even more genes for kidney disease. In the past year, this work has lead to the discovery of several new loci for renal function and related traits. An important publication was the identification of a missense SNP the CUBN gene in association with albuminuria. Albuminuria is a significant and independent predictor of chronic kidney disease progression and cardiovascular morbidity and mortality in the general population. Identification of genetic risk factors for albuminuria may alter strategies for early prevention of disease progression, particularly among patients with diabetes. Little is known about the influence of common genetic variants on albuminuria in both general and diabetic populations. We performed a meta-analysis of data from 63,153 individuals of European ancestry with genotype information from genome-wide association studies (CKDGen consortium) and from a large candidate gene study (CARe consortium) to identify susceptibility loci for the quantitative trait urinary albumin-to-creatinine ratio (UACR) and the clinical diagnosis microalbuminuria. Findings were verified in 6,981 participants of African ancestry in the CARe Consortium, as well as in a prospective study of patients with type I diabetes (DCCT/EDIC). These findings identify a missense SNP in the CUBN gene that is associated with levels of urinary albumin in both the general population and individuals with diabetes and highlight the potential role of shared genetic susceptibility for albuminuria in diverse clinical settings. This work has also evolved into sequencing, and the CHARGE-S consortium is sequencing 400 cases of chronic kidney disease. Dr. Fox has set up collaboration with a zebra fish lab to begin to understand the functional consequences of some newly uncovered loci for renal function. This has resulted in a recent publication, which highlights Dr. Foxs translational work. We performed an interrogation of known renal loci, genome-wide association (GWA), and IBC candidate-gene SNP association analyses in African Americans from the CARe Renal Consortium. We performed meta-analyses of GWA and IBC array data for estimated glomerular filtration rate (eGFR), CKD, urinary albumin-to-creatinine ratio (UACR), and microalbuminuria and interrogated the 250kb flanking region around 24 SNPs previously identified in European Ancestry renal GWAS analyses. Findings were replicated in up to 4358 African Americans. To assess function, individually identified genes were knocked down in zebrafish embryos by morpholino antisense oligonucleotides. Functional genetic studies support a role for in glomerular development in zebrafish. Diabetes Finally, Dr. Fox works in the area of diabetes, primarily to understand trends in diabetes as a risk factor for heart disease, as well as treatment patterns over time. Dr. Fox is currently working on a lifecourse analysis to understanding the evolution of CVD risk factors associated with diabetes.